Screening for rectal and pharyngeal infection due to Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) is crucial for sexually transmitted disease (STD) control in men who have sex with men (MSM). Extragenital infections account for most GC and CT cases among MSM and are almost always asymptomatic. Women who have receptive anal and oral sex with men can acquire extragenital infection just as MSM can, which raises the question of whether we should allocate public health resources to detecting extragenital infections in women.
The report from Trebach and colleagues1 in this issue moves us closer to answering that question. The investigators studied the clinical epidemiology of extragenital GC and CT infection among women, MSM, and men who have sex with women only in 2 public STD clinics in Baltimore, Maryland. The clinics implemented pharyngeal screening for all patients who reported exposure through oral sex and implemented rectal screening for all patients who reported receptive penile-anal sex, oral-anal sex, or shared sex toys in the preceding 3 months. The report focuses on patients with isolated extragenital infections, that is, rectal and pharyngeal infections without concurrent genital infection. This is the most relevant outcome for program planning because isolated extragenital infections in women would not be ascertained with standard urogenital testing.
For 2 years, the Baltimore STD clinics screened 4402 women for GC or CT infection of the pharynx or rectum. Of these, 57 (approximately 2%) had isolated extragenital CT and 50 (approximately 1%) had isolated extragenital GC. These infections accounted for 14% of the 412 total CT and 30% of the 165 total GC infections in women. During the same period, the clinics tested 769 MSM, in whom extragenital infections were substantially more common compared with women. Rectal CT was the most common extragenital infection in women, and the prevalence of rectal CT was less disparate between women and MSM (9% vs. 14%) compared with rectal and pharyngeal GC. These results, taken together with previous studies summarized in a table in the article, indicate that 10% to 25% of all CT and 20% to 40% of all GC cases in women are missed with standard cervicovaginal or urine screening.
The study by Trebach and colleagues enhances the literature on extragenital infections in women because it compares both pharyngeal and rectal infections due to both CT and GC in both women and MSM. Many previous studies on this topic did not directly compare infections in women and MSM, did not determine which extragenital infections were isolated, or limited testing to 1 pathogen or 1 anatomical site. With the addition of this article and 2 others recently published,2,3 the compendium of literature clearly demonstrates a few points. First, women contract extragenital GC and CT infections. Although investigators have raised the possibility of false positives or cross-contamination, several studies have found rectal and pharyngeal infections in women who did not have infection at another anatomical site, including what seems to be the earliest report of extragenital gonorrhea in women.4 Second, nongenital infections in women, particularly rectal chlamydia, are not rare. Although they are much less prevalent in women than MSM, they are sufficiently frequent to raise the question of whether routine screening is indicated. Third, systematic efforts to screen women for extragenital infection increase the detection of GC and CT.
However, the mere presence of extragenital infection is not what impacts prevention strategies or clinical management. Rather, the key questions are what clinical harm women's extragenital infections cause, whether screening averts that morbidity, and whether the averted morbidity is worth the cost. In addition, how important are extragenital infections for sustained transmission at the population level? Should screening be restricted to women in geographic areas or subpopulations with the highest prevalence of GC and CT, and if so, what prevalence threshold would make screening worthwhile? In other words, we now know that if we screen women for extragenital infection, we will find it, but why should we?
General criteria for evaluating a screening test provide a framework for considering extragenital screening in women.5 The value of a screening program depends on characteristics of the test and the disease. The test should be capable of detecting the disease at an early stage, safe, widely available at reasonable cost, and demonstrated to lead to improved health outcomes. Nucleic acid amplification testing for extragenital screening in women probably meets all of these criteria, except the last. To be a candidate for asymptomatic screening, a disease should constitute a significant public health problem (a common condition with significant morbidity or mortality) and have a readily available treatment that increases the potential for cure with early detection. Extragenital infections in women are relatively simple to cure, but whether the infections constitute a significant public health problem is unclear.
Sexually transmitted disease researchers have rigorously studied the impact of screening for cervical CT infection on health outcomes in women.6,7 Although data in support of screening are not unassailable, the consensus in the field is that screening can prevent pelvic inflammatory disease, ectopic pregnancy, and infertility.8 Is the goal of extragenital screening in women also to prevent the sequelae of cervical infection, either for the index patient or for her partners' other partners? Or is it the same as for MSM, namely, to diminish the incidence of GC and CT and to avert HIV acquisition and transmission?
If the primary rationale for extragenital screening in women is to prevent the sequelae of cervical infection, we need to determine whether rectal infection is associated with persistent or recurrent cervical infections. To definitively answer that question, we need direct evidence from a prospective study. Lacking that, we can extrapolate from other studies. Nonrandomized studies of MSM strongly suggest that azithromycin is less effective than doxycycline for treating rectal infection.9 This corroborates animal studies demonstrating that azithromycin is less effective at clearing Chlamydia muridarum from the gastrointestinal tract than the cervix.10,11 If doxycycline is truly more effective than azithromycin for treating rectal CT, and if concurrent rectal-cervical infection truly causes persistent cervical infection, then we would expect doxycycline to be more effective for the treatment of cervical CT. Indeed, a recent meta-analysis of randomized controlled trials of urogenital CT treatment found that doxycycline was more effective than azithromycin, but the difference was so small as to be clinically inconsequential (2.6% [95% confidence interval, 0.5%–4.7%]) and did not differ between women and men.12 This suggests that screening women for rectal CT might not have a substantial public health impact.
Alternatively, the rationale for extragenital screening in women could be the same as it is MSM. First, extragenital screening might prevent male partners from acquiring symptomatic urethritis. However, we know that MSM acquire urethral infection from the rectums and pharynges of their partners through simple deduction: that is the only way they can get it. Men who have sex with women only, on the other hand, mostly acquire urethritis through vaginal sex. Anal sex in the absence of vaginal sex is an uncommon behavior among heterosexuals, and thus, women's rectums are not isolated reservoirs as men's are.13 Transmission from the pharynx might be different, and we need to better understand the relative epidemiologic importance of pharyngeal versus rectal infections in women. Second, we screen MSM for extragenital infection to decrease the risk of HIV infection. At least in the United States, improving screening in MSM must be a higher priority than implementing extragenital screening for women for the purpose of HIV prevention. Men who have sex with men are at substantially higher risk than women for HIV and extragenital infection and are underscreened even in STD clinics.14
Trebach's group analyzed predictors of isolated extragenital infection in women with the goal of informing targeted screening. They found that age <18 years was the strongest and most consistent risk factor. However, only women who reported anal sex were screened for rectal infection in this study. Although an exposure-driven screening approach is rational and aligned with other STD screening practices, it might be the wrong approach for rectal chlamydia. A recent study reported that prevalence of rectal CT in women who did not report anal sex was comparable to that in women who reported anal sex,2 confirming the results of an earlier study.15 Women may underreport anal sex, but if that was the sole explanation for rectal CT in women without anal exposure, we would expect at least some level of association between the exposure and the infection. Rank and Yeruva11,16 recently proposed an intriguing alternate explanation: the gastrointestinal tract can become colonized by chlamydiae through either oral or rectal inoculation and remain infected in the absence of clinical disease, much as it does in other animals, thereby acting as a reservoir for autoinoculation and persistent infection. Targeting rectal screening for women based on reported anal sex, although intuitive, is not supported by the available evidence.
In summary, Trebach and coworkers provided crucial data on the epidemiology of extragenital infections in women seeking care in STD clinics. The key questions now are what clinical harm these infections cause, whether we can avert that morbidity through screening, and how to target screening resources most effectively to the women at highest risk for infection. Answering those questions will allow us to make an informed decision about whether, and which, women need screening for extragenital GC and CT infections.
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